Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Listeriolysin O (LLO) is a pore-forming cytolysin secreted by the pathogen Listeria monocytogenes and is required for its intracellular survival. We recently demonstrated that in endothelial cells, LLO activates the NF-kappaB signalling pathway. In this work, we studied the LLO-induced molecular cascade of NF-kappaB activation with a cellular model extensively used to analyse the signalling pathway of NF-kappaB activation, i.e. the human embryonic kidney HEK-293 cell line and its derivatives (transfectants or mutants). When the stably transfected derivative HEK-293 cells expressing IL-1RI were exposed to LLO, a strong NF-kappaB activation was detected, contrasting with other cell lines (HEK-293 wild type, HEK-293.T and COS) expressing a very low level of IL-1RI. Although a delayed kinetics of LLO-dependent NF-kappaB activation suggests an autocrine or paracrine IL-1-dependent pathway, we found that LLO-dependent NF-kappaB activation did not require the IL-1 protein synthesis nor the interaction with the IL-1RI specific receptor. Herein, we demonstrated that LLO-dependent NF-kappaB activation requires the activation of the IkappaB kinase beta (IKKbeta) subunit of IKK complex to phosphorylate and degrade cytoplasmic IkappaBalpha, a natural inhibitor of NF-kappaB. The activation induced by LLO does not require the adapters MyD88 and IL-1R-associated kinase (IRAK). We suggested that LLO induces a distinct signalling pathway from that of IL-1 and its receptor.
Mol Microbiol 2002 Jun
PMID:Listeriolysin O secreted by Listeria monocytogenes induces NF-kappaB signalling by activating the IkappaB kinase complex. 1202 84

To examine the potential role of particle iron in fibrogenicity, we loaded nonfibrogenic fine (0.12micro) TiO(2) with increasing amounts of Fe(II)-Fe(III) chloride. Dusts were applied to rat tracheal explants, which were maintained in air organ culture for 1 wk. Iron-loaded dust increased procollagen gene expression and tissue hydroxyproline. The active oxygen species (AOS) scavenger tetramethylthiourea prevented these effects. Iron loading caused nuclear factor (NF)-kappaB activation, decreased levels of total IkappaBalpha, but relatively increased levels of both IkappaBalpha-phosphoserine 32/36 and IkappaBalpha-phosphotyrosine. A citrate extract of iron-loaded dust increased procollagen expression. Gel shift using a probe consisting of the NF-kappaB consensus sequence from the prolyl-4-hydroxylase promoter and adjacent bases showed increased nuclear binding, and RT-PCR examination showed increased prolyl-hydroxylase alpha-chain gene expression after iron loading. We conclude that addition of surface iron can convert a nonreactive model air pollutant particle into a fibrogenic particle via AOS- and NF-kappaB-dependent pathways, probably through two different NF-kappaB activation pathways in two different anatomic compartments. This process may proceed in vivo through iron extracted from the dust into the cytoplasm. NF-kappaB activation may directly increase expression of prolyl hydroxylase, an enzyme involved in collagen synthesis. These findings suggest that air pollutant particles containing significant quantities of transition metals may produce airway wall fibrosis and lead to chronic obstructive pulmonary disease.
Am J Respir Cell Mol Biol 2002 Jun
PMID:Iron loading makes a nonfibrogenic model air pollutant particle fibrogenic in rat tracheal explants. 1203 67

The acute inflammatory response has been triggered in rat lungs by deposition of IgG immune complexes. The inflammatory reaction triggered is highly tissue damaging and requires activation of NF-kappaB with ensuing generation of chemokines and cytokines. Endogenous generation of IL- 10 and IL- 13 as well as secretory leukocyte protease inhibitor (SLPI), significantly regulates this inflammatory response. IL-10 and IL-13 attenuate NF-kappaB activation by interfering with breakdown of IkappaBalpha, while SLPI likewise suppresses NF-kappaB activation, but by interfering with breakdown of IkappaBbeta. Antibody induced blockade of IL-10, IL-13 or SLPI enhances NF-KB activation in lung and exacerbates the lung inflammatory response and injury. These data indicate that endogenous IL-10, IL-13 and SLPI are important regulators of the inflammatory response by reducing gene activation with resultant generation of peptide mediators/cytokines and chemokines.
Mol Cell Biochem
PMID:Endogenous regulation of the acute inflammatory response. 1216 38

Using a system that expresses a constitutively kinase-active c-Abl protein [c-Abl(KA)], we identified the protein IkappaBalpha as a novel substrate of c-Abl. This kinase-substrate relationship is not only confirmed at the level of endogenous proteins but is also supported by a physical interaction between the two proteins. Interestingly, the association of c-Abl with IkappaBalpha, which is detectable in the form of nonphosphorylated proteins, is remarkably enhanced by an inducible binding of tyrosine-phosphorylated IkappaBalpha to the c-Abl SH2 domain. In contrast to the serine 32/34 phosphorylation that triggers ubiquitination and degradation of IkappaBalpha, c-Abl-mediated phosphorylation at tyrosine 305 is associated with an increase of the IkappaBalpha protein stability. Significantly, this activity is not shared by the oncogenic Bcr-Abl, because it is unique to the nuclear c-Abl. We also demonstrate that c-Abl targets the nuclear subpopulation of IkappaBalpha for phosphorylation and induces it to accumulate in the nucleus. As a consequence, NF-kappaB transcription activity is abolished, leading to an increased cellular sensitivity to the induction of apoptosis. The functional importance of c-Abl-mediated IkappaBalpha phosphorylation is highlighted by a loss of response of the IkappaBalpha(Y305F) protein to c-Abl-mediated regulation. Using cells expressing the c-Abl(KA) protein under the control of an inducible promoter, we demonstrate inactivation of the NF-kappaB-dependent cell survival pathway as one of the mechanisms for c-Abl-mediated apoptosis.
Mol Cell Biol 2002 Sep
PMID:Inactivation of NF-kappaB-dependent cell survival, a novel mechanism for the proapoptotic function of c-Abl. 1216 2

Amentoflavone, a biflavonoid with antiinflammatory activity, downregulates COX-2 expression in TNFalpha-activatedA549 cells with concomitant inhibition of NF-kappaB mediated signaling cascades. We demonstrate here that amentoflavone inhibits NF-kappaB/ DNA binding activity potently along with inhibition of degradation of IkappaBalpha and NF-kappaB translocation into nucleus in TNFalpha-activated A549 cells. This flavonoid upregulates PPAR gamma, a transcription factor involved in repressing many cytokine-induced gene expressions. Hence amentoflavone, a dietary constituent, may be of therapeutic value for several lung diseases where COX-2 plays an important role.
Mol Cell Biochem 2002 Sep
PMID:Inhibition of TNFalpha-induced cyclooxygenase-2 expression by amentoflavone through suppression of NF-kappaB activation in A549 cells. 1234 96

The glucocorticoid and progesterone receptors (GR and PR) are structurally homologous and bind a common hormone response element (HRE). The mechanisms by which receptors activate specific promoters when multiple steroids are present in a cell is a critical question in endocrinology. To investigate how co-existing steroid receptors regulate gene transcription, we have compared two hormone-responsive promoters in T47D/A1-2 human breast cancer cells expressing both the GR and PR. The promoters chosen were those for the mouse mammary tumor virus (MMTV) and the gene for IkappaBalpha, the inhibitor of the ubiquitous transcription factor, nuclear factor kappa B (NFkappaB). Several differences between glucocorticoid and progestin activation of the IkappaBalpha and MMTV promoters were revealed. Both steroids activated the endogenous IkappaBalpha promoter, while only glucocorticoids activated a stably integrated MMTV promoter. In combination, progestins enhanced glucocorticoid activation of IkappaBalpha, but antagonized glucocorticoid activation of MMTV. These differences in steroid receptor competition were further demonstrated when levels of the PR were reduced by prolonged treatment with progestin. Under these conditions, the PR no longer competes effectively with the GR for activation of the MMTV promoter. However, on the IkappaBalpha promoter, the GR and PR still activate the promoter in a cooperative fashion. Another difference between the two promoters is their chromatin structure. In this cell line, the MMTV promoter chromatin is "closed" and insensitive to restriction enzyme cleavage, while the IkappaBalpha promoter is "open." Using PR antagonists, we demonstrate that at least one cofactor complex, the BRG-1 chromatin remodeling complex, differentially contributes to activation of both promoters.
J Steroid Biochem Mol Biol 2002 Aug
PMID:Differential activation of the IkappaBalpha and mouse mammary tumor virus promoters by progesterone and glucocorticoid receptors. 1236 20

We previously reported that exposure of mice to hyperoxia is characterized by extensive lung cell necrosis and apoptosis, mild inflammatory response, and elevated circulating levels of corticosterone. Administration of hydroxycortisone acetate during hyperoxia aggravated lung injury. Using adrenalectomized (ADX) and sham-operated (sham) mice, we studied the role of the glucocorticoids in hyperoxia-induced lung injury. Lung damage was attenuated in ADX mice as measured by lung weight and protein and cell content in bronchoalveolar lavage and as seen by light microscopy. Mortality was delayed by 10 h. Nuclear factor-kappaB (NF-kappaB) activity was significantly decreased in lungs of sham mice exposed to hyperoxia but was preserved in ADX mice. There was a correlation between NF-kappaB activity in ADX mice and decreased levels of IkappaBalpha. In contrast, activator protein-1 activity increased similarly in both groups of mice. Levels of interleukin-6 (IL-6), a transcriptional target of NF-kappaB, were higher in bronchoalveolar lavage and serum of ADX than sham mice. However, the protective effect of ADX was not mediated by IL-6, because administration of recombinant human IL-6 to sham mice did not prevent lung damage. These results demonstrate that the adrenal response aggravates alveolar injury and is likely to be mediated by the decrease of NF-kappaB function involved in cell survival.
Am J Physiol Lung Cell Mol Physiol 2003 Jan
PMID:Glucocorticoids aggravate hyperoxia-induced lung injury through decreased nuclear factor-kappa B activity. 1238 43

IkappaBalpha inhibits transcription factor NF-kappaB activity by specific binding to NF-kappaB heterodimers composed of p65 and p50 subunits. It binds with slightly lower affinity to p65 homodimers and with significantly lower affinity to homodimers of p50. We have employed a structure-based mutagenesis approach coupled with protein-protein interaction assays to determine the source of this dimer selectivity exhibited by IkappaBalpha. Mutation of amino acid residues in IkappaBalpha that contact NF-kappaB only marginally affects complex binding affinity, indicating a lack of hot spots in NF-kappaB/IkappaBalpha complex formation. Conversion of the weak binding NF-kappaB p50 homodimer into a high affinity binding partner of IkappaBalpha requires transfer of both the NLS polypeptide and amino acid residues Asn202 and Ser203 from the NF-kappaB p65 subunit. Involvement of Asn202 and Ser203 in complex formation is surprising as these amino acid residues occupy solvent exposed positions at a distance of 20A from IkappaBalpha in the crystal structures. However, the same amino acid residue positions have been genetically isolated as determinants of binding specificity in a homologous system in Drosophila. X-ray crystallographic and solvent accessibility experiments suggest that these solvent-exposed amino acid residues contribute to NF-kappaB/IkappaBalpha complex formation by modulating the NF-kappaB p65 subunit NLS polypeptide.
J Mol Biol 2002 Dec 06
PMID:Solvent exposed non-contacting amino acids play a critical role in NF-kappaB/IkappaBalpha complex formation. 1246 May 63

IkappaBalpha and IkappaBbeta are regulators of the nuclear factor-kappaB (NF-kappaB) transcription factor family. Both IkappaBs bind to the same NF-kappaB dimers and are widely expressed in different cells and tissues. To better understand how these two IkappaB isoforms differ biologically, we have characterized the expression of IkappaBbeta in testis, a tissue in which IkappaBalpha is only minimally expressed. We have found that IkappaBbeta expression is localized within the haploid spermatid stages of spermatogenesis and follows the expression of nuclear NF-kappaB. IkappaBbeta expression in haploid spermatids is likely regulated by Sox family proteins, members of which are also expressed within spermatids. We have shown that both SRY and Sox-5 can bind to multiple Sox binding sites found within the IkappaBbeta promoter and can enhance transcription of a reporter gene in transient transfection assays. We also demonstrate that IkappaBbeta mRNA is strongly expressed in developing male gonads. These results therefore suggest that IkappaBbeta may be a novel target for transcription factors of the HMG-box SRY/Sox family and imply a potential role for NF-kappaB/IkappaBbeta in spermatogenesis.
Mol Biol Cell 2002 Dec
PMID:Regulation of IkappaBbeta expression in testis. 1247 44

NF-kappaB1 p105 functions both as a precursor of NF-kappaB1 p50 and as a cytoplasmic inhibitor of NF-kappaB. Following the stimulation of cells with tumor necrosis factor alpha (TNF-alpha), the IkappaB kinase (IKK) complex rapidly phosphorylates NF-kappaB1 p105 on serine 927 in the PEST region. This phosphorylation is essential for TNF-alpha to trigger p105 degradation, which releases the associated Rel/NF-kappaB subunits to translocate into the nucleus and regulate target gene transcription. Serine 927 resides in a conserved motif (Asp-Ser(927)-Gly-Val-Glu-Thr-Ser(932)) homologous to the IKK target sequence in IkappaBalpha. In this study, TNF-alpha-induced p105 proteolysis was revealed to additionally require the phosphorylation of serine 932. Experiments with IKK1(-/-) and IKK2(-/-) double knockout embryonic fibroblasts demonstrate that the IKK complex is essential for TNF-alpha to stimulate phosphorylation on p105 serines 927 and 932. Furthermore, purified IKK1 and IKK2 can each phosphorylate a glutathione S-transferase-p105(758-967) fusion protein on both regulatory serines in vitro. IKK-mediated p105 phosphorylation generates a binding site for betaTrCP, the receptor subunit of an SCF-type ubiquitin E3 ligase, and depletion of betaTrCP by RNA interference blocks TNF-alpha-induced p105 ubiquitination and proteolysis. Phosphopeptide competition experiments indicate that betaTrCP binds p105 more effectively when both serines 927 and 932 are phosphorylated. Interestingly, however, betaTrCP affinity for the IKK-phosphorylated sequence on p105 is substantially lower than that on IkappaBalpha. Thus, it appears that reduced p105 recruitment of betaTrCP and subsequent ubiquitination may contribute to delayed p105 proteolysis after TNF-alpha stimulation relative to that for IkappaBalpha.
Mol Cell Biol 2003 Jan
PMID:betaTrCP-mediated proteolysis of NF-kappaB1 p105 requires phosphorylation of p105 serines 927 and 932. 1248 91


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